BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines Journal Article

   

Authors:	Leboeuf, R.; Baumgartner, J. E.; Benezra, M.; Malaguarnera, R.; Solit, D.; Pratilas, C. A.; Rosen, N.; Knauf, J. A.; Fagin, J. A.
Article Title:	BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines
Abstract:	Context: Mutually exclusive mutations of RET, RAS, or BRAF are present in about 70% of papillary thyroid carcinomas, whereas only the latter two are seen in poorly differentiated and anaplastic cancers. Although the signal output common to these oncoproteins is ERK, a recent report showed that only BRAF mutations consistently predicted responsiveness to MAPK kinase (MEK) inhibitors. Objectives: Here we investigated whether sensitivity to MEK inhibition was determined by oncogene status in 13 human thyroid cancer cell lines: four with BRAF mutations, four RAS, one RET/ PTC1, and four wild type. Results: Growth of BRAF (+) cells was inhibited by the MEK antagonist PD0325901 with an IC 50 of less than 5nM. By contrast, RAS, RET/PTC1, or wild-type cells had IC50 of 4 nM to greater than 1000nM. Sensitivity was not predicted by coexisting mutations in PIK3CA or by PTEN status. Similar effects were obtained with the MEK inhibitor AZD6244. PD0325901 induced a sustained G1/S arrest in BRAF (+) but not BRAF (-) lines. PD0325901 was equipotent at inhibiting pERK1/2 after 2 h, regardless of genetic background, but pERK rebounded at 24 h in most lines. MEK inhibitor resistance was associated with partial refractoriness of pERK to further inhibition by the compounds. AZD6244 was more potent at inhibiting growth of NPA (BRAF +) than Cal62 (KRAS +) xenografts. Conclusion: Thyroid cancers with BRAF mutation are preferentially sensitive to MEK inhibitors, whereas tumors with other MEK-ERK effector pathway gene mutations have variable responses, either because they are only partially dependent on ERK and/or because feedback responses elicit partial refractoriness to MEK inhibition. Copyright © 2008 by The Endocrine Society.
Keywords:	controlled study; protein phosphorylation; gene mutation; human cell; genetics; missense mutation; mutation, missense; nonhuman; antineoplastic agents; antineoplastic agent; cell proliferation; mouse; animal; animals; mice; cell cycle s phase; drug inhibition; enzyme inhibition; protein kinase inhibitor; animal experiment; animal model; cancer cell culture; tumor xenograft; drug effect; drug resistance; drug screening; enzymology; drug resistance, neoplasm; xenograft model antitumor assays; cell line, tumor; protein kinase inhibitors; oncogene; drug antagonism; nude mouse; mice, nude; substrate specificity; tumor cell line; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; carcinoma; drug derivative; mitogen activated protein kinase 1; mitogen activated protein kinase 3; cell cycle arrest; ras protein; thyroid cancer; thyroid neoplasms; enzyme specificity; fluorescence activated cell sorting; protein ret; b raf kinase; thyroid tumor; oncogene ras; mitogen activated protein kinase kinase; mitogen-activated protein kinase kinases; cell cycle g1 phase; 5 (4 bromo 2 chloroanilino) 4 fluoro 1 methyl 1h benzimidazole 6 carbohydroxamic acid 2 hydroxyethyl ester; protein patched 1; benzimidazole derivative; benzimidazoles; proto-oncogene proteins b-raf; braf protein, human; n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide; benzamide derivative; benzamides; diphenylamine; oncogene ptc1; oncogene reti
Journal Title:	Journal of Clinical Endocrinology and Metabolism
Volume:	93
Issue:	6
ISSN:	0021-972X
Publisher:	Oxford University Press
Date Published:	2008-06-01
Start Page:	2194
End Page:	2201
Language:	English
DOI:	10.1210/jc.2007-2825
PUBMED:	18381570
PROVIDER:	scopus
PMCID:	PMC2435640
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-45149098960&partnerID=40&md5=f17c3715f1fc6117b0b1cc76106910f0
Notes:	--- - "Cited By (since 1996): 50" - "Export Date: 17 November 2011" - "CODEN: JCEMA" - "Source: Scopus"

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